rs4624987

Positions:

• chr8-32539186-G-A
• chr8-32539186-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000520407.5(NRG1):​c.746-56642G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,212 control chromosomes in the GnomAD database, including 2,213 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (2213 hom., cov: 33)
• Consequence: NRG1 ENST00000520407.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0580

Genes affected

NRG1 (HGNC:7997): (neuregulin 1) The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRG1	NM_001159995.3	c.38-56642G>A		intron_variant			NP_001153467.1
NRG1	NM_001159999.3	c.38-56642G>A		intron_variant			NP_001153471.1
NRG1	NM_001160001.3	c.38-56642G>A		intron_variant			NP_001153473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRG1	ENST00000520407.5	c.746-56642G>A		intron_variant		1		ENSP00000434640
NRG1	ENST00000519301.6	c.38-56642G>A		intron_variant		5		ENSP00000429582
NRG1	ENST00000523534.5	c.305-56642G>A		intron_variant		5		ENSP00000429067

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16281 AN: 152094 Hom.: 2199 Cov.: 33

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0879

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.0986

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0917

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.107 AC: 16321 AN: 152212 Hom.: 2213 Cov.: 33 AF XY: 0.109 AC XY: 8148 AN XY: 74424

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.0883

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.583

Gnomad4 SAS AF: 0.0982

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.0893

Alfa AF: 0.0358 Hom.: 103

Bravo AF: 0.122

Asia WGS AF: 0.255 AC: 886 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.4
DANN	Benign	0.59

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4624987; hg19: chr8-32396704;